Selectfluor and alcohol-mediated synthesis of bicyclic oxyfluorination compounds by Wagner–Meerwein rearrangement

Herein, we report the first environmentally friendly systematic fluoroalkoxylation reactions in bicyclic systems. New oxyfluorination products were obtained with excellent yields (up to 98%) via Wagner–Meerwein rearrangement using benzonorbornadiene and the chiral natural compound (+)-camphene as bicyclic alkenes, selectfluor as an electrophilic fluorine source, and water and various alcohols as nucleophile sources. The structure of bicyclic oxy- and alkoxyfluorine compounds was determined by NMR and QTOF-MS analyses.


Introduction
Organofluorines are of great importance in the pharmaceutical and agrochemical industries, as the presence of fluorine has a serious effect on the biological activities of organic compounds by changing their metabolic stability, hydrogen bonding ability, lipophilicity, solubility, bioavailability, conformation and general structure [1][2][3][4].About 20% of commercially available drugs contain fluorine, and this ratio is estimated to increase further [5,6].Among organofluorines, oxyfluorines are an important subclass used as an active ingredient in many different drugs such as fludrocortisone (the first fluorine-containing commercial drug) [7,8], sofosbuvir (antihepatitis C) [9], dexamethasone (to treat ashma, severe allergies) [10], difluprednate (ocular anti-inflammatory) [11,12] and many more (Figure 1).On the other hand, with unusual geometry and high reactivity  norbornadiene and benzonorbornadiene derivative bicyclic compounds attract great attention by researchers with their use as building blocks in different application areas such as polymers, solar energy storage materials, supramolecular and bioactive compounds [13][14][15][16][17].To the best of our knowledge, although the oxyfluorination of various olefins with water and alcohols is known in the literature [18][19][20][21][22][23][24][25][26], there is no systematic study on the oxyfluorination of bicyclic alkenes.We previously developed a dihomohalogenation method using selectfluor as an oxidant [27].Herein, we synthesized bicyclic oxyand alkoxyfluorine compounds using selectflour as an electrophilic fluorination reagent, water and various alcohols as an nucleophile.

Results and Discussion
In this study, benzonorbornadiene (1a) and the chiral natural product (+)-camphene (1b) were used as bicyclic alkenes.Safe, easily soluble, easy to use, stable solid, reactive and commercial available selectfluor [18,27,28] was selected for electrophilic fluorination source.Water and various alcohols were used as nucleophiles.First, optimization experiments were carried out for fluoroalkoxy reactions with benzonorbornadiene (1a, Table 1).As a result of experiments conducted in six different solvents at Scheme 1: Oxyfluorination of benzonorbornadien (1a) with Selectfluor and alcohols.All reactions were carried out using 0.5 mmol of benzonorbornadiene (1a), 0.6 mmol of selectfluor, and 1.2 mmol alcohol in 2 mL of CH 3 CN at 90 °C for 2 h.Isolated yields.
room temperature with 1.0 equivalent of selectflor and 1.0 equivalent of methanol, it was observed that there was a 12% conversion with CH 3 CN and a 10% conversion with nitromethane, while no conversion occurred with the other solvents including, CH 2 Cl 2 , EtOAc, 1,4-dioxane and DMF (Table 1, entries 1-6).To see the effect of reactant ratios on yields, when reactants were gradually increased at room temperature, the best result was obtained with 1.2 equivalents of selectfluor and 2.4 equivalents of methanol with 21% conversion (Table 1, entry 7).There was no significant change at higher equivalents.At 50 °C, 30% conversion was achieved with 1.2 equivalents of selectfluor and 2.4 equivalents of methanol for one hour, while at 90 °C, a 67% conversion was obtained (Table 1, entries 8 and 9).Finally, when the reaction time was increased to two hours at 90 °C, the product was obtained with a 98% conversion (Table 1, entry 10).
In order to demonstrate the gram-scale applicability of fluoroalkoxylation reactions in bicyclic systems using optimized reaction conditions with (+)-camphene (1b, 1.0 g, 7.34 mmol), scale-up experiments were conducted.The isolated yield of 4b (1.26 g, 90% yield) is quite satisfactory, as can be seen from Scheme 3.
For the fluoroalkoxylation, we propose the mechanism given in Scheme 4. In this mechanism, first the double bond in Scheme 2: Oxyfluorination of (+)-camphene (1b) with selectfluor and alcohols.All reactions were carried out using 0.5 mmol of (+)-camphene, 0.6 mmol of selectfluor, and 1.2 mmol alcohol in 2 mL of CH 3 CN at 90 °C for 2 h.Isolated yields.

Scheme 4:
Proposed mechanism for fluoroalkoxylation of (+)-camphene by Wagner-Meerwein rearrangement.(+)-camphene attacks the fluorine in the selectfluor and a carbocation is formed by bonding with fluorine.Subsequently, fluoroalkoxy compound 4 is formed by Wagner-Meerwein rearrangement followed by alcohol addition and deprotonation.

Conclusion
New bicyclic fluoroalkoxy compounds were synthesized by a molecular fluorine and metal-free methodology.An environmentally friendly approach was pursued by using safe, easily soluble, easy to use, stable, solid and reactive selectfluor as an electrophilic fluorination reagent, and water and various alcohols as a nucleophile source.Besides being novel, the presented oxyfluorination protocol provides distinct advantageous such as (i) the methodology does not require the presence of any metal moities, (ii) enables the synthesis of corresponding oxyfluorinated analogues with high yields and selectivity, (iii) allows derivatization of natural chiral molecules, (iv) uses a safe solvent in mild reaction parameters.We hope that these potentially biologically active bicyclic fluoroalkoxy compounds will find a place in various application areas in biological systems.

Table 1 :
Optimizing the conditions for the oxyfluorination of bicyclic alkenes a .